Clinical outcome of myelodysplastic syndrome progressing on hypomethylating agents with evolving frontline therapies: continued challenges and unmet needs

INTRODUCTION Hypomethylating agents (HMA) are the standard treatment of patients with higher risk MDS with overall response rates in the range of 30 – 40% [1, 2]. A signi ﬁ cant proportion of patients progressing after HMA therapy transform to AML. The majority of these patients carry adverse risk chromosomal/molecular features, are older, ineligible for intensive therapies, and therefore, have a poorer prognosis [3, 4]. While CPX-351 compared to 3 + 7 demonstrated improved outcome in AML patients with myelodysplastic related changes (MRC), there was no signi ﬁ cant difference in overall survival (OS) in patients who received prior HMA therapy (5.7 vs 5.9 months) [5]. The azacitdine plus venetoclax combination compared to azacitdine alone demonstrated improve survival in patients with secondary AML, however in the pivotal study, previous receipt of any HMA, venetoclax, or chemotherapy for MDS was exclusionary [6]. We sought to explore outcome of MDS patients progressing after HMA therapy in the era of novel therapies utilizing real world data. METHODS This is a retrospective study that includes 71 MDS patients progressing on HMA therapy and treated at the Mayo Clinic. The study was conducted after institutional review board approval. Clinical details including baseline characteristics including cyto- genetics (CG) and molecular data, treatment after HMA progression and clinical outcome abstracted from electronic medical records of patients treated at Mayo Clinic between February 2015 and February 2021. Mutation analysis was performed on bone marrow specimens using a 42 gene targeted next generation sequencing (NGS) panel. Responses were assessed according to the International Working Group (IWG) response criteria for MDS and AML [7, 8]. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). risk MDS and secondary AML. In our study patient who achieved remission and underwent alloHCT had signi ﬁ cantly better OS, however it did not retain signi ﬁ cance for better OS in multivariate analysis. TP53 mutated high risk MDS/AML are considered high risk disease with poor response to therapy and dismal outcome [10]. Similarly, in our analysis in the era of novel therapies, TP53 mutation retained poor prognostic signi ﬁ cance with a dismal median OS of 2.6 months after progressing on HMA. We report our institutional experience of clinical outcome of MDS patients progressing after HMA in the era of novel therapies. Response rate and survival outcome are still modest, effective therapies are needed to improve outcome of these high-risk patients.


INTRODUCTION
Hypomethylating agents (HMA) are the standard treatment of patients with higher risk MDS with overall response rates in the range of 30-40% [1,2]. A significant proportion of patients progressing after HMA therapy transform to AML. The majority of these patients carry adverse risk chromosomal/molecular features, are older, ineligible for intensive therapies, and therefore, have a poorer prognosis [3,4]. While CPX-351 compared to 3 + 7 demonstrated improved outcome in AML patients with myelodysplastic related changes (MRC), there was no significant difference in overall survival (OS) in patients who received prior HMA therapy (5.7 vs 5.9 months) [5]. The azacitdine plus venetoclax combination compared to azacitdine alone demonstrated improve survival in patients with secondary AML, however in the pivotal study, previous receipt of any HMA, venetoclax, or chemotherapy for MDS was exclusionary [6]. We sought to explore outcome of MDS patients progressing after HMA therapy in the era of novel therapies utilizing real world data.

METHODS
This is a retrospective study that includes 71 MDS patients progressing on HMA therapy and treated at the Mayo Clinic. The study was conducted after institutional review board approval. Clinical details including baseline characteristics including cytogenetics (CG) and molecular data, treatment after HMA progression and clinical outcome was abstracted from electronic medical records of patients treated at Mayo Clinic between February 2015 and February 2021. Mutation analysis was performed on bone marrow specimens using a 42 gene targeted next generation sequencing (NGS) panel. Responses were assessed according to the International Working Group (IWG) response criteria for MDS and AML [7,8]. Continuous variables were summarized as median (range), while categorical variables were reported as frequency (percentage). Predictors of treatment response were assessed by Chi-square or Fisher's exact test for nominal data and Wilcoxon rank-sum test for continuous variables. Overall survival from the date of HMA progression till last follow up or death was evaluated by the Kaplan-Meier method with differences compared by the log-rank test. Cox proportional hazards regression models were used to find the univariate and multivariate predictors of overall survival. Multivariable models included all significant univariate predictors with p value < 0.1.

Response
Among patients with MDS-EB1/MDS-EB2 (n = 23), 7 (30%) patients achieved complete remission (CR) and 2 (9%) had marrow CR. Among 42 AML patients who progressed after HMA therapy and received induction chemotherapy, 36% of patients achieved CR/ CR with incomplete count recovery (i) (n = 8 CR, n = 7 CRi). Five (10%) out of 48 patients who progressed to AML, did not received induction chemotherapy due to poor performance and inadequate organ functions. Overall, 14 (20%) patients progressing on HMA successfully bridge to alloHCT. Apart from age ≥ 70 years (p = 0.02), there was no significant difference in baseline characteristics, mutation profile and treatment received on HMA progression among patients who achieved CR/CRi and received alloHCT versus no alloHCT (Supplementary Table 1).

DISCUSSION
We presented our experience on outcome of patients with MDS progressing on HMA therapy in the current era. The clinical outcome of patients has improved modestly compared to historical data [3] and patients who achieved complete remission, retained significance for better OS in multivariate analysis.
Azacitdine plus venetoclax based therapy has been a paradigm shift in the management of patients with AML who are ineligible for intensive therapies [6]. Moreover, a recently conducted phase I study, also demonstrated promising efficacy and durable response of the azacitidine plus venetoclax combination in patients with high risk MDS [9]. In our cohort, a venetoclax-based regimen were associated with better OS after HMA progression, however, it did not retain significance in multivariate analysis, most likely due to the heterogenous patient population with a higher proportion of patients harboring TP53 mutation, having t-MDS, which is distinct from patients in clinical trials. Similar, to what has been reported in the randomized study, we did not observe significant benefit of CPX-351 in achieving remission or improving OS in this group of patients [5].
AlloHCT is the only potential curative option for patients with high risk MDS and secondary AML. In our study patient who achieved remission and underwent alloHCT had significantly better OS, however it did not retain significance for better OS in multivariate analysis. TP53 mutated high risk MDS/AML are considered high risk disease with poor response to therapy and dismal outcome [10]. Similarly, in our analysis in the era of novel therapies, TP53 mutation retained poor prognostic significance with a dismal median OS of 2.6 months after progressing on HMA.
We report our institutional experience of clinical outcome of MDS patients progressing after HMA in the era of novel therapies. Response rate and survival outcome are still modest, effective therapies are needed to improve outcome of these high-risk patients.